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首页> 外文期刊>Journal of Pharmaceutical and Biomedical Analysis: An International Journal on All Drug-Related Topics in Pharmaceutical, Biomedical and Clinical Analysis >Metabonomics study on orthotopic transplantion mice model of colon cancer treated with Astragalus membranaceus-Curcuma wenyujin in different proportions via UPLC-Q-TOF/MS
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Metabonomics study on orthotopic transplantion mice model of colon cancer treated with Astragalus membranaceus-Curcuma wenyujin in different proportions via UPLC-Q-TOF/MS

机译：用UPLC-Q-TOF / MS在不同比例中用黄芪治疗的结肠癌原位移植小鼠模型的代谢组学研究

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摘要

Metabolomics, an important part of systems biology, can reveal the complex pathogenesis of many diseases and mechanism of Chinese materia medica (CMM). Astragalus membranaceus-Curcuma wenyujin (AC) was a classic drug pair that has a good clinical effect on gastrointestinal inflammation and many tumors. Our previous research proved that AC can inhibit tumor growth and metastasis especially the colorectal cancer (CRC), also promote the normalization of tumor blood vessels, but its optimal ratio and the specific mechanism is still not clear. In this study, colon cancer mice of orthotopic transplantion model was used to screen the best proportion, UPLC-Q-TOFIMS metabolomics analysis method was established to explore the pathogenesis of colon cancer and the molecular mechanism of AC. The correlation analysis of metabolite changes and tumor growth was analyzed by R language. The result showed that AC at the ratio of 2:1 showed the best effect on inhibiting tumor growth, also the liver and spleen metastasis rate. A total of 23 potential biomarkers were detected in the serum of colon cancer mice by the analysis of Progenesis QI (Version 2.4) software. Among this, 11 metabolites including purines, steroids, phytosphingosine and 1-palmitoylcarnitine were up-regulated in CC mice, while 12 metabolites like amino acids, deoxyribose and dihydrobiopterin were down-regulated in CC mice. After the treatment of AC for 15 days, 8 biomarkers were up-regulated, and 9 biomarkers down-regulated. Especially, AC at the ratio of 2:1 showed a significant callback effect on metabolic biomarkers, such as hypoxanthine, xanthosine, 7-methylxanthine, all-trans-retinoic acid, dihomo-gamma-linolenic acid. 8 metabolic pathways: Aminoacyl-tRNA biosynthesis, Nicotinate and nicotinamide metabolism, Phenylalanine, tyrosine and tryptophan biosynthesis, Valine, leucine and isoleucine biosynthesis, Phenylalanine metabolism, Caffeine metabolism, Retinol metabolism, Alanine, aspartate and glutamate metabolism were selected as the model group disturbed metabolic pathways after the enrichment of MetaboAnalyst 4.0 online analysis software. And compared with the model group, Valine, leucine and isoleucine biosynthesis, Aminoacyl-tRNA biosynthesis, Caffeine metabolism pathway and Retinol metabolism pathways were altered after the intervention of AC. The correlation analysis results showed that various endogenous metabolites in serum have a strong correlation with tumor weight, such as hypoxanthine, which provides a basis for the selection of clinical markers. The results showed that AC can partially regulate metabolic disorder of CC mice by reversing the changes of metabolites, so as to inhibit the growth and metastasis of colon cancer, especially at the ratio of 2:1. These findings can provide a scientific basis for exploring the diagnostic biomarkers of colon cancer, and for clinical application of AC in the treatment of CRC program. (C) 2020 Published by Elsevier B.V.
机译：代谢组学是系统生物学的重要组成部分，可以揭示多种疾病的复杂发病机制和中药的作用机制。黄芪温郁金是治疗胃肠道炎症和多种肿瘤的经典药物。我们以前的研究证明AC可以抑制肿瘤生长和转移，尤其是结直肠癌（CRC），也可以促进肿瘤血管的正常化，但其最佳比例和具体机制尚不清楚。本研究采用结肠癌小鼠原位移植模型，筛选最佳比例，建立UPLC-Q-TOFIMS代谢组学分析方法，探讨结肠癌的发病机制和AC的分子机制，用R语言分析代谢产物变化与肿瘤生长的相关性。结果表明，2:1的AC对肿瘤生长的抑制效果最好，对肝、脾转移的抑制率也最好。通过ProgenesQI（2.4版）软件分析，在结肠癌小鼠血清中检测到23种潜在的生物标志物。其中包括嘌呤、类固醇、植物鞘氨醇和1-棕榈酰肉碱在内的11种代谢物在CC小鼠中上调，而氨基酸、脱氧核糖和二氢生物蝶呤等12种代谢物在CC小鼠中下调。AC治疗15天后，8个生物标志物上调，9个生物标志物下调。尤其是，2:1的AC对代谢生物标记物，如次黄嘌呤、黄嘌呤、7-甲基黄嘌呤、全反式维甲酸、二高-γ-亚麻酸，表现出显著的回调效应。8代谢途径：氨酰-tRNA生物合成、烟酸和烟酰胺代谢、苯丙氨酸、酪氨酸和色氨酸生物合成、缬氨酸、亮氨酸和异亮氨酸生物合成、苯丙氨酸代谢、咖啡因代谢、视黄醇代谢、丙氨酸、，在MetaboAnalyst 4.0在线分析软件富集后，选择天门冬氨酸和谷氨酸代谢为干扰代谢途径的模型组。与模型组相比，AC干预后缬氨酸、亮氨酸和异亮氨酸生物合成、氨酰-tRNA生物合成、咖啡因代谢途径和视黄醇代谢途径发生改变。相关分析结果表明，血清中的各种内源性代谢产物与肿瘤重量有很强的相关性，如次黄嘌呤，为临床标志物的选择提供了依据。结果表明，AC可通过逆转代谢产物的变化，部分调节CC小鼠的代谢紊乱，从而抑制结肠癌的生长和转移，尤其是在2:1的比例下。这些发现为探索结肠癌的诊断生物标志物，以及AC在结肠癌治疗中的临床应用提供了科学依据。（C） 2020年爱思唯尔公司出版。

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